Abstract
Skin irritation is a complex phenomenon, and keratinocytes play an important role in it. We have recently characterized the expression and protective role of adipose differentiation related protein (ADRP) in skin irritation. In particular, ADRP expression is induced to recover functional cell membrane following the cell damage caused by skin irritants. The purpose of this study was to characterize in a human keratinocyte cells line (NCTC 2544) the biochemical events that lead to ADRP expression following SDS treatment, and in particular, to investigate the role of transcription factor SP-1. Analysis of ADRP promoter region revealed the presence of a potential binding site for the transcription factor SP-1 close to the start site. Evaluated by measuring the DNA binding activity, we found that SDS induced a dose and time related SP-1 activation, which was correlated with SDS-induced ADRP mRNA expression. Furthermore, SDS-induced SP-1 activation, ADRP mRNA expression and lipid droplets accumulation could be modulated by mithramycin A, an antibiotic that selectively binds to the GC box preventing SP-1 binding and gene expression. This demonstrated that SDS-induced ADRP expression was mediated in part through the transcription factor SP-1. In addition, SDS-induced SP-1 activation and ADRP expression could be modulated by the calcium chelator BAPTA, indicating a role of calcium in ADRP-induction. Thus, every time an irritant perturbs the membrane barrier, it renders the membrane leaky and allows extracellular calcium to enter the cells, an event that provides the upstream mechanisms initiating the signaling cascade that triggers the activation of SP-1 and culminates in the enhancement of ADRP expression, which helps to restore the normal homeostasis and ultimately repairs the to membrane.
Highlights
Skin irritation is, from both a clinical and a mechanistic perspective, a multifaceted disease
In order to understand the role of transcription factor SP-1 in SDS-induced adipose differentiation related protein (ADRP) expression, we first assessed the ability of SDS to induce SP-1 activation
SDSinduced SP-1 activation reached a maximum after 45 min, and returned to control values after 180 min (Fig. 1A), while SDS-induced ADRP mRNA expression started after 1 h of treatment and increased thereafter (Fig. 1C)
Summary
From both a clinical and a mechanistic perspective, a multifaceted disease. In the last two decades, it has become clear that keratinocytes, which represent 95% of epidermal cells, play an important role in initiating and maintaining skin inflammatory and immunological reactions. We have identified in human keratinocytes the upregulation of adipose differentiation related protein (ADRP) by skin irritants (Corsini et al 2002). ADRP is a lipid droplet protein found in most cells and tissues, which has an important role in management of neutral lipid stores, both in deposition and mobilization (Heid et al 1998). Intracellular neutral lipid storage droplets are essential cytosolic organelles of eukaryotic cells used mainly as energy source and for membrane biogenesis (Brasaemle et al 1997; Miura et al 2002). Lipid droplets provide fatty acids for signaling/ gene regulation, fatty acids and glycerides for membrane phospholipid synthesis, as well as, fatty acids to produce energy (Brown, 2001)
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